The present invention relates to the treatment of heart disease using cyclooxygenase-2 (COX-2) inhibiting drugs. Heart disease can be congenital or caused by an initial precipitating insult. Examples of initial insults include a lack of adequate blood flow, infection, toxins and autoimmune type reactions. Typically cardiac function continues to deteriorate post-initial insult, and heart muscle (myocyte) performance declines.
The term "heart disease" is used in the general sense and includes conditions ranging, for example, from those in which positive inotropic medications are useful to those in which coronary vessel occlusion is predominant, to arrhythmias or cardiotoxicity, such as that which may be observed as a side effect of cardiotoxic drugs, e.g., doxorubicin. In these conditions, it is evident that COX-2 expression and the inflammation that is attendant therewith contribute to the overall disease state.
Congestive heart failure (CHF, cardiac failure) is a form of heart disease in which weakened heart function exists with concommitant edema. Congestive heart failure has many different causes, including narrowing of the arteries supplying blood to the heart muscle (coronary heart disease); prior heart attack (myocardial infarction) resulting in scar tissue large enough or located so to interfere with normal electrocardiac function; high blood pressure; heart valve disease, such as due to past rheumatic fever or congenital valve abnormality; primary disease of the heart muscle itself (cardiomyopathy); other defects in the heart present at birth (congenital heart disease); and infection of the heart valves and/or heart muscle itself (endocarditis and/or myocarditis). Each of these disease processes can lead to congestive heart failure.
Congestive heart failure is one of the most serious cardiovascular diseases affecting adults. Over 4 million people have congestive heart failure, and the incidence is on the rise. The incidence of this disease or condition is increasing with the aging of the population and is currently the most common cause for hospital admission in the elderly. The total U.S. healthcare expenditure on CHF is over five billion dollars per year.
Congestive heart failure results in systolic left ventricular dysfunction and sodium and water retention. This is most commonly due to myocardial infarction, but can also be due to pressure or volume overload, viral infection, an autoimmune process or direct toxins. After this initial insult, the disease often progresses due to poorly understood mechanisms. These mechanisms are believed to involve localized inflammatory responses involving nitric oxide release and its local production, COX-2 expression, immune mediators and inflammatory cytokines.
Current therapies for CHF are aimed at interrupting the systemic effects of CHF without addressing the myocardial process directly. There is now evidence that the progression of heart failure is mediated by inflammatory mechanisms. For example, cytokines and other inflammatory mediators have been shown to be elevated in CHF and are increased at the tissue level. In addition, matrix metalloproteinases, which are involved in many types of inflammatory and reparative responses are also involved in the adverse remodeling of the myocardium in CHF.
Consequently one object of the present invention is to treat or prevent heart disease by inhibiting the sequelae that are caused by COX-2 expression in the heart.
Another object of the present invention is to potentiate the effect of conventional agents that are used in the treatment or prevention of heart disease.
These and other objects will become obvious from the description provided herein.